Oral adminstration of borage and echium oils to subjects with asthma results in a decreased capacity for leukotriene (LT) generation by peripheral blood leukocytes. This is a potentially important outcome in terms of explaining the therapeutic benefits of botanical oils, but the mechanisms(s) responsible are not known. The major goal ofthis Project is to precisely define these mechanism(s) in human cells that are relevant to the pathophysiology of asthma. In Aim 1, we will determine whether supplementation with borage and echium oils impairs PI-3K signaling in basophils, neutrophils, and monocytes in the blood of patients with asthma, and whether this translates into diminished production of pathophysiologically important lipid mediators and cytokines. In Aim 2, we will determine whether supplementation with borage and echium oils shifts the profile of PG production by peripheral blood monocytes from PGE2 and thromboxane A2 (TXA2) (a powerful bronchoconstrictor) to PGE1, a mediator that has been proposed to have potent anti-inflammatory properties. We will also determine the dominant cyclooxygenase (COX) and PGE synthase (PGES) isoforms responsible for the generation of PGE1, and whether dietary supplementation with borage and echium oils uprgulates the expression and function of PPARy in peripheral blood monocytes due to a loss of suppressive Pl-3K/Akt signaling from endogenous PGE2. Upregulation of the expression and function of PPARy would be expected to reduce ainway inflammation in asthmatic subjects through suppression of transcription of proinflammatory cytokines. These studies will complement the studies in Project 1 (J. Parks) that focus on the ability of botanical oils to facilitate the development of a vasoprotective PPARy-driven macrophage phenotype. Lastly, in Aim 3, we will determine the anti-asthmatic potential of PGE1 and determine its receptor utilization based on its ability to "stabilize" human MOs. The latter studies are essential because of the critical nature of MC activation in both the initiation and perpetuation of airway inflammation in asthma. These studies are highly integral to the PPG as a whole, and will shed substantial light onto the mechanistic basis for the efficiacy of botanical oils in asthma and other inflammatory disorders.